p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFß signaling.

Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-ß and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

Toxicidad por interferón alfa y neuropatía óptica bilateral reversible: una retirada a tiempo / Interferon-alpha toxicity and reversible bilateral optical neuropathy: A timely withdrawal of the drug

CASO CLÍNICO: Paciente que acude por pérdida crónica de visión bilateral indolora en el que destaca el uso de Interferón alfa (IFNα) y ribavirina para un trasplante hepático. Con un fondo de ojo normal, la sospecha de neuropatía óptica retrobulbar viene confirmada por la prolongación de la latencia de los potenciales evocados visuales. Sin antecedentes de riesgo y con un estudio sistémico normal, la mejoría clínica y de las pruebas electrofisiológicas tras retirar el fármaco señalan al IFNα como causa de la afectación del nervio óptico bilateral. DISCUSIÓN: El IFNα es un tratamiento usado en enfermedades virales y neoplásicas. Actualmente es formulado como Interferón alfa pegilado (IFNα-p) para reducir toxicidad y mejorar su tolerancia. Sus efectos secundarios más comunes son síndrome gripal, astenia y pérdida de peso. La afectación ocular es rara y la neuropatía óptica es una complicación infrecuente siendo más frecuente la retinopatía en el inicio del tratamiento. La hipótesis más aceptada como causa de la toxicidad es la existencia de complejos inmunes circulantes. Así pues es de vital importancia para el oftalmólogo conocer la toxicidad de este fármaco para saber retirar a tiempo el mismo, evitando una posible pérdida visual irreversible

CLINICAL CASE: A patient with chronic, painless, bilateral loss of vision, after significant intake of interferon (IFNα) and ribavirina due to liver transplant. Ocular fundus is normal. A suspected retrobulbar optic neuropathy is confirmed by a prolongation of the latency of the patient's visual evoked potential. There being no prior record of risk factors and with the patient's systemic analysis giving normal results, the clinical improvement and the electro-physiological tests conducted after the drug was withdrawn point to interferon as negatively affecting the bilateral optic nerve. Discussion: Interferon-α is used in the treatment of viral and neoplastic illnesses. Currently the drug is formulated as Interferon alfa pegilado (IFNα-p) in order to reduce toxicity and increase tolerance. The most common secondary effects are flu symptoms, asthenia and weigh loss. Affected ocular tissue is rare and optic neuropathy is also an infrequent complication: retinopathy at the beginning of treatment is, however, more frequent. The most widely accepted hypothesis as to the cause of toxicity is the presence of circulating immune complexes. It is, therefore, essential for ophthalmologists to be aware of the toxicity of this drug in order to be able to withdraw it in good time, thus preventing potentially irreversible sight loss

[Interferon-alpha toxicity and reversible bilateral optical neuropathy: a timely withdrawal of the drug]. / Toxicidad por interferón alfa y neuropatía óptica bilateral reversible: una retirada a tiempo.

Clinical case A patient with chronic, painless, bilateral loss of vision, after significant intake of interferon (IFNα) and ribavirina due to liver transplant. Ocular fundus is normal. A suspected retrobulbar optic neuropathy is confirmed by a prolongation of the latency of the patient's visual evoked potential. There being no prior record of risk factors and with the patient's systemic analysis giving normal results, the clinical improvement and the electro-physiological tests conducted after the drug was withdrawn point to interferon as negatively affecting the bilateral optic nerve. Discussion Interferon-α is used in the treatment of viral and neoplastic illnesses. Currently the drug is formulated as Interferon alfa pegilado (IFNα-p) in order to reduce toxicity and increase tolerance. The most common secondary effects are flu symptoms, asthenia and weigh loss. Affected ocular tissue is rare and optic neuropathy is also an infrequent complication: retinopathy at the beginning of treatment is, however, more frequent. The most widely accepted hypothesis as to the cause of toxicity is the presence of circulating immune complexes. It is, therefore, essential for ophthalmologists to be aware of the toxicity of this drug in order to be able to withdraw it in good time, thus preventing potentially irreversible sight loss.

p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53.

The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/- and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic target.

Mieloma múltiple con manifestaciones cutáneas / Cutaneous manifestation in multiple myeloma

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[Neurophysiological monitoring in the treatment of pain]. / Monitorización neurofisiológica en la terapia del dolor.

INTRODUCTION: The concept of transynaptic deafferentation secondary to a lesion is the basis of the therapeutic criteria of functional neurosurgery. DEVELOPMENT: Pain due to deafferentation requires clinical neurophysiological techniques for characterization, and when appropriate, for localization of the level of the lesion and the ectopic focus or foci which cause the pain syndrome. However, monitoring therapeutic interventions in the pain clinic is an ever increasing need, and obliges the clinical neurophysiologist to master the range of techniques involved in his specialty, so that he can use the most suitable techniques and methods as required by each condition and/or case. The use of techniques such as micro-recordings of the unitary or multiunitary activity of the nerves or nuclei, intracerebral evoked potentials, nociceptive evoked potentials, reflexology, polysomnography and topography, together with techniques such as percutaneous objective localization of deep nerves, allows quantitative evaluation pre-, intra- and postoperative. CONCLUSION: The development of neuromodulation, and in particular of acute or long-term neurostimulation by use of percutaneous techniques, offers an effective therapeutic option in the field of clinical neurophysiology.

Monitorización neurofisiológica en la terapia del dolor / Neurophysiological monitoring in the treatment of pain

Introducción. El concepto de desaferentización transináptica secundaria a una lesión es la base del criterio terapéutico de la neurocirugía funcional. Desarrollo. El dolor por desaferentización requiere de las técnicas de la neurofisiología clínica para su caracterización y, en su caso, para la localización del nivel lesivo y del foco o focos ectópicos que pueden estar generando el síndrome de dolor. Sin embargo, la monitorización de las intervenciones terapéuticas en la clínica del dolor constituye una demanda cada vez mayor, que obliga al neurofisiólogo clínico a dominar la globalidad de técnicas que conforman su especialidad, con la finalidad de implementar ante cada proceso y/o cada caso en particular las técnicas y metodologías apropiadas y adecuadas. La implementación de técnicas como el microrregistro de la actividad unitaria o multiunitaria de nervios o núcleos, los potenciales evocados intracerebrales, los potenciales evocados nociceptivos, la reflexología, la polisomnografía y topografía, junto a técnicas como la localización objetiva percutánea de nervios en profundidad, permiten la valoración cuantitativa pre, intra y postintervención. Conclusión. La evolución de la neuromodulación y, en particular, la neuroestimulación subaguda o crónica, mediante la utilización de técnicas percutáneas, abren un camino de impacto para el ejercicio profesional del neurofisiólogo clínico en el ámbito terapéutico (AU)